tbuckley/cabot-search huggingface dataset:
CSIG-05. A FIRST COMPREHENSIVE ANALYSIS OF TRANSCRIBED ULTRA CONSERVED REGIONS UNCOVERS IMPORTANT REGULATORY FUNCTIONS OF NOVEL NON-CODING TRANSCRIPTS IN GLIOMAS
Authors: Myron Gibert, Shekhar Saha, Ying Zhang, Pawel Pawel Marcinkiewicz, Bilhan Chagari, Christian Roig-Laboy, Aditya Sarkar, Collin Dube, Kadie Hudson, Yunan Sun, Benjamin Kefas, Roger Abounader
Journal: Neuro-Oncology (2023)

Abstract Most glioma research has focused on protein-coding genes and much less on non-coding RNAs (ncRNAs). Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of ncRNAs that are highly conserved across multiple species, including 100% conservation in mouse and rat genomes. These 481 transcripts are highly resistant to variation and are commonly deregulated in cancer, which suggests regulatory and functional importance when considered along with their high degree of conservation. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We first annotated all TUCRs in gliomas and described their genomic locations. We then showed that numerous TUCRs are highly expressed and deregulated in gliomas, and that this deregulation is associated with clinical outcomes. We then used a WGCNA pipeline to predict the functions for all TUCRs in gliomas by compiling gene ontology (GO) terms for coregulated genes. These data were used to identify several TUCRs that are potentially relevant to glioma initiation and progression. Of these, we investigated the most highly upregulated intergenic TUCR, uc.110, in vitro and in vivo in GBM. Knockdown of uc.110 in vitro reduced GBM cell accumulation and invasion and knockdown in vivo inhibited GBM xenograft growth and increased animal survival. We then performed mechanistic analyses of uc.110 and found that it regulates the expression of a Wnt pathway member, membrane frizzled-related protein (MFRP). We discovered that uc.110 sponges the tumor suppressor microRNA miR-544, which targets and inhibits MFRP, thus increasing the bioavailability of MFRP in GBM. This study is the first of its kind in gliomas. It shows important regulatory roles for TUCRs in gliomas and outlines novel methods for studying TUCRs in any disease context.
RADT-01. BASELINE HIPPOCAMPAL VOLUME AS A PREDICTOR OF NEUROCOGNITIVE CHANGES AFTER WBRT OR HA-WBRT: SECONDARY ANALYSIS OF NRG ONCOLOGY CC001
Authors: Christopher Abraham, Stephanie Pugh, Paul Brown, Vinai Gondi, Joseph Bovi, Clifford Robinson, Jeffrey Wefel, David Roberge, Vijayananda Kundapur, Kiran Devisetty, Sunjay Shah, Kenneth Usuki, Andrew Baschnagel, Baldassarre Stea, Harold Yoon, Jing Li, Nadia Laack, Saurahb Jindal, Monica Borges, Lisa Kachnic
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Hippocampal volume (HV) is a predictor of neurocognitive function (NCF) in neurodegenerative disease. The role of patient-specific anatomic variables has not been well investigated in patients with brain metastases. This work aimed to evaluate HV at baseline and 6 months as a predictor of NCF and differential benefit from HA-WBRT for patients enrolled on CC001. MATERIALS HV was calculated at baseline and 6 months. HV at baseline and 6 months were correlated with baseline and 2, 4, and 6-month NCF scores (HVLT-R Total and Delayed Recall, Delayed Recognition, TMT Parts A and B, and COWA) using Pearson correlation. Correlation was defined as weak if ρ ≤0.35. A cox proportional hazards model was used to determine the impact of baseline HV on time to NCF failure. RESULTS Of 518 patients randomized on CC001, 277 had baseline imaging, and 135 had 6-month imaging. However, only 87 patients were analyzable at both baseline and 6-month periods. At baseline, HV was not significantly associated with NCF score for any measure (p-value range: 0.06-0.72). Additionally, there was no association between baseline HV and time to NCF failure (p = 0.16). Additionally, the impact of treatment arm allocation on HV was examined but found to be non-significant (p = 0.06). Lastly, baseline HV and NCF scores were noted to have weak correlation at 2, 4, 6, and 12 month timepoints (ρ: range, -0.17-0.15; P-value range, 0.04-0.98). At 6 months, the correlation between HV, baseline NCF change, and 6 month standardized NCF change were also noted to be weak (ρ: range, 0.05-0.16; P-value range, 0.06-0.76). CONCLUSIONS Radiotherapy is known to have deleterious effects on neurocognition. In neurodegenerative disease, HV and rate of HV change are known predictors for NCF. However, baseline HV is not an independent predictor of neurocognitive changes after WBRT or HA-WBRT for patients with brain metastases.
EPCO-45. CELLULAR HIERARCHIES OF ETMR ARE SHAPED BY ONCOGENIC MICRORNAS AND RECEPTOR-LIGAND INTERACTIONS
Authors: Lisa Gabler, Alexander Beck, Gustavo Cruzeiro, Sander Lambo, Bernhard Englinger, McKenzie L Shaw, Olivia Hack, Susan Chi, Sanda Alexandrescu, Johannes Gojo, Marcel Kool, Volker Hovestadt, Mariella Filbin
Journal: Neuro-Oncology (2023)

Abstract Embryonal tumor with multilayered rosettes (ETMR) is a highly aggressive brain tumor that predominantly occurs in children under the age of four years. Most children succumb within 10 months of diagnosis, typically due to invasive tumor growth and therapy-refractory behavior. 95% of ETMR harbor activating genetic alterations of the chromosome 19 microRNA cluster (C19MC). Despite the identification of this presumed oncogenic driving event, its biological consequences remain understudied and targeted therapy options are lacking. Here, we set out to further explore the intracellular heterogeneity of ETMR and shed light onto its oncogenic mechanisms with the goal to identify novel therapeutic targets for this dismal disease. We have compiled and analyzed a cohort of 11 ETMR tumors using single-cell RNA sequencing and multiplexed spatial imaging. We reveal a common, spatially distinct cellular hierarchy, closely resembling physiological brain development. This hierarchy spans a highly proliferative neural stem cell-like population that gives rise to more differentiated neuron-like cells. C19MC, predominantly expressed in the malignant stem-like population, controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA interactions. Targeting specific C19MC members by antisense oligonucleotides results in reduced cell proliferation, suggesting potent new avenues for future therapeutic approaches. Seeking more immediate therapeutic targets, we performed comprehensive cell-cell interaction analyses and reveal that FGF-FGFR and Delta-Notch interactions are important to maintain oncogenic signaling across malignant cell populations. These interactions were successfully targeted using small molecule inhibitors in preclinical models and in one ETMR patient. Taken together, we identify different malignant ETMR cell populations that follow a common developmental hierarchy, explore the regulatory reach of C19MC activation, and identify an oncogenic receptor-ligand interaction network. Targeting this interaction network opens a powerful new rationale for more effective ETMR therapies.
EOLP-05. SUPPLEMENTAL ENTERAL NUTRITION DOES NOT IMPROVE SURVIVAL IN OLDER PATIENTS WITH PRIMARY MALIGNANT BRAIN TUMORS
Authors: Margaret O Johnson, Alice Parish, Seth M Cohen, Donna Niedzwiecki, Katherine Peters, David A Leiman
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The risk of dysphagia increases with age and is prevalent among older adults with primary malignant brain tumors (PMBTs). As a result, patients with PMBTs may receive supplemental enteral nutrition (EN) but its impact on outcomes is uncertain. Therefore, we compared survival among Medicare beneficiaries with PMBTs and dysphagia by use of EN. METHODS We analyzed a Medicare 5% limited data set from 2013-2018. We included beneficiaries ≥65 years with PMBTs and solid tumors (lung, breast, melanoma, renal, and colorectal) identified by ICD9/10 codes. Predisposing conditions for dysphagia were excluded. To assess differences in survival of dysphagic patients by EN access (i.e., gastrostomy tube), hazard ratios and 95% confidence intervals (CI) from a Cox proportional-hazards model were calculated after adjusting for age, sex, race, and Elixhauser Comorbidity Index (ECI). RESULTS The rate of dysphagia among 79,926 beneficiaries was 4.7% (n=3,777), and significantly higher among those with PMBTs (11%, p&amp;lt; 0.01) compared to solid organ tumors with (8.0%) and without brain metastases (4.4%). Among patients with PBMTs, the presence of dysphagia was associated with lower survival compared to those without dysphagia (p&amp;lt; 0.001). For patients with PMBT and dysphagia, adjusted models showed no significant difference (p=0.08) in survival among those who received EN (N=78) compared to those that did not (N=271); however, those with EN had a 33% higher hazard of death compared to those without EN [HR= 1.34, 95% CI: (0.99, 1.81)]. CONCLUSION Dysphagia is common among older patients with brain cancer and disproportionally affects those with PMBTs. The use of EN in this population-based study of Medicare beneficiaries did not significantly improve survival and there was a trend toward harm. Given the frequency of EN use and observed worse outcomes, further validation in a larger clinical dataset is warranted.
INNV-10. GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS – EXPERIENCE OF CASES PRESENTED AT NATIONAL AYA MULTI-DISCIPLINARY ROUNDS
Authors: Julie Bennett, Natalie Massey, Sunit Das, Seth Climans, Maria MacDonald, Sébastien Perreault, Magimairajan Issai Vanan, Stephen Yip, Sarah Lapointe, Derek Tsang, Uri Tabori, Cynthia Hawkins, Mary-Jane Lim-Fat
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Gliomas are the most common brain tumor in adolescents and young adults (AYA). IDH mutations are common in this population, though up to 30% of gliomas in AYA harbor a pediatric-type alteration including alterations in RAS/MAPK pathway and histone mutations. These can present a diagnostic and management dilemma in young adults given the limited data in this population. Here, we aim to describe glioma cases submitted for multi-disciplinary AYA rounds. METHODS Gliomas presented at the Canadian AYA Neuro-Oncology Network (CANON) rounds between April 2021 and June 2023 were compiled. Patient demographics, tumor histology and molecular alterations are described. Recommendations and themes from the multi-disciplinary rounds were summarized. RESULTS Of 132 cases presented, 96 were gliomas. Median age was 28 years (range 15-59). Twelve (12.5%) cases were IDH-mutant. Remaining cases included low grade glioma (LGG, n=37, 38.5%), IDH-WT high grade gliomas (HGG, n=22, 22.9%) and diffuse midline glioma (n=13, 13.5%). Of the LGGs, 13 gliomas had FGFR-alteration, 9 had BRAF-alteration, 3 had NF-1 with 4 having rare alterations typically seen in children (KRAS, NTRK fusion, PDGFRa K385-mut). Recommendations included discussion to start targeted therapy or management of toxicities due to targeted inhibitors in 16 cases. Of the HGGs, 7 (31.8%) had underlying cancer predisposition syndrome (NF-1 n=4, mismatch repair deficiency n=3). Management questions included role of re-resection, timing of radiation, duration of targeted therapies and access to targeted agents through clinical trials or compassionate access programs. CONCLUSION Within national rounds, there was enrichment of pediatric-type tumors and patients with cancer predisposition syndromes. Targeted agents are available for many of these driver mutations with potential improved outcomes; however, access to these agents in AYA may be limited. Clinicians face complex management questions in this population and underscores the need for a multi-disciplinary approach along with clinical trial opportunities for these patients.
PATH-36. CLASSIFICATION OF DIFFUSE GLIOMA SUBTYPES USING A NEXT-GENERATION SEQUENCING PANEL IN ACCORDANCE WITH THE 2021 WORLD HEALTH ORGANIZATION CRITERIA
Authors: Yongjae Kim, Dohoon Park, Hwan Park, Kang-Seo Park, Chang Ohk Sung, Ji Eun Park, Shinkyo Yoon, Ho-Su Lee
Journal: Neuro-Oncology (2023)

Abstract Diffuse gliomas, which are the most common primary brain tumors, exhibit significant variations in their characteristics such as morphology, location, genetic alterations, and response to treatment. In 2021, the World Health Organization (WHO) introduced updated guidelines for glioma classification based on molecular alterations. This study aimed to classify 476 primary diffuse glioma samples utilizing a next-generation sequencing OncoPanel AMC, targeted DNA sequencing, in accordance with the 2021 WHO criteria. The samples were divided into 3 subtypes: oligodendroglioma (ODG; n=70), diffuse astrocytoma (DA; n=65), and glioblastoma (GBM; n=341). The median age of patients diagnosed with GBM (62 years) was significantly higher compared to those with ODG (50 years) and DA (42 years) (Page=0.056 [ODG vs.DA], 3.06×10-11 [ODG vs.GBM], and 3.06×10-11 [DA vs.GBM]). Gender and tumor mutational burden did not exhibit significant associations with the subtypes. Consistent with the 2021 WHO criteria, ODG samples exhibited frequent mutations in IDH1 (91%), NOTCH1 (27%), FUBP1 (23%), CIC (20%), and IDH2 (9%). DA samples had a high prevalence of mutations in IDH1 (98%), TP53 (91%), ATRX (78%), and IDH2 (2%). In contrast, GBM samples showed mutations in IDH-wildtype and EGFR (18%). Cox multivariate regression analysis of 341 GBM patients (median survival=15.9 months) revealed that older age, lack of MGMT promoter methylation, and impaired performance status (Karnofsky performance scale&amp;lt; 80) were significantly associated with survival outcome (HRage=1.40, Page=7.64×10-3, HRMGMT=1.43, PMGMT=6.98×10-3, and HRKPS=1.79, PKPS=3.05×10-6). In summary, by utilizing the AMC OncoPanel and the 2021 WHO criteria, we successfully classified diffuse glioma into three distinct.
BIOM-02. CSF LIQUID-BASED DIAGNOSIS OF LEPTOMENINGEAL DISEASE (LMD) FROM NON-SMALL CELL LUNG CANCER (NSCLC) USING DDPCR AGAINST EGFR MUTATIONS
Authors: Kay Ka-Wai Li, Jackie Mei-Wah Fung, Peter Yat-Ming Woo, Anthony Pak-Yin Liu, Chit Chow, Ho-Keung Ng
Journal: Neuro-Oncology (2023)

Abstract Leptomeningeal disease (LMD) due to spreading of solid cancers to the leptomeninges has a very poor prognosis and is poorly diagnosed. MR imaging may be negative and CSF cytology, the gold standard, is not sensitive enough, due to small number of cells inherent in CSF, small volume and inter-observer variability in microscopy. We tested the hypothesis that cfDNA from CSF could be a unique source of DNA from LMD which can be used for diagnosis as well as research. We collected 39 CSF samples from patients suspected of LMD from NSCLCs. CfDNA was extracted by cobas® cfDNA Sample Preparation Kit. Hotspot EGFR mutations (G719X, S768I, T790M, C797S, L858R, L861Q, and 19 del) were tested by multiplexed droplet-digital PCR (ddPCR). EGFR mutation status of the original primary NSCLCs were previously tested for by real-time PCR using formalin-fixed paraffin-embedded tissues. Six samples did not yield sufficient DNA. For the remaining 33 cases, EGFR mutations were detected in 16 samples. For fifteen of these positive cases, identical mutations were found in the matched tissue samples. EGFR status of one primary tumor was unknown. Cytology was negative in 10 cases, atypical in five and only positive in one case. For the 17 negative samples, in 11 cases, the corresponding tumor tissues lacked EGFR mutations. Five patients from the negative group were eventually found not to have LMD. Only in one case was the lung tissue found to have EGFR mutation but mutation was not found in CSF cfDNA. In a few selected cases, we studied the genomics of the cfDNA together with the primary tumor tissues with low-pass WGS and similar CNVs were found in both. CSF cfDNA is a unique source of DNA from LMD and can be used as a useful tool in clinical diagnosis and research.
CNSC-35. EVALUATING THE THERAPEUTIC POTENTIAL OF NOVEL NTRK AGONISTS AND ANTAGONISTS IN HIGH-RISK NEUROBLASTOMA
Authors: David Johnson, Thomas Schlichthaerle, Siobhan Pattwell, David Baker
Journal: Neuro-Oncology (2023)

Abstract Neuroblastoma is the most common extra-cranial tumor diagnosed in children within the first two years of their lives. Although low-risk and intermediate -risk neuroblastoma patients have a survival rate of 90-95%, high-risk neuroblastoma patients have a survival rate of approximately 50%. To improve the survival rate in high-risk patients, our group focuses on tropomyosin receptor kinases (TRKs), which are family of tyrosine kinases that have been heavily implicated in crucial developmental processes, such as differentiation, that are typically hijacked in cancer. Using de novo agonists specifically designed against three different neurotrophin receptors (TrkA, TrkB, TrkC), our group is investigating the fundamental biological role of TRK receptors in mediating tumorigenesis in neuroblastoma. Preliminary results show that our TrkA agonist not only increase both ERK and AKT activity but also causes a significant decrease in TrkA expression in several neuroblastoma cell lines which we hypothesize is due to constitutive activation of TrkA, leading to its internalization and degradation. Phenotypically, we observe that neuroblastoma cell line SK-N-SY5Y, which is typically used in differentiation studies, lose their neuroblast-like phenotype when treated with TrkA agonist, and begin to exhibit neurite outgrowth which may be indicative of differentiation-associated pathways being activated due to TrkA activation. Using a combination of de novo protein design, immunoblotting, RNA-sequencing, and in vivo studies to characterize the effect(s) TRK agonists have on neuroblastoma, we hope to assess whether targeting and modifying the activity of TrkA, and other Trk receptors such as TrkB and TrkC, holds new therapeutic promise for patients with high-risk neuroblastoma.
CTNI-05. INTRATHECAL PEMETREXED FOR LEPTOMENINGEAL METASTASES FROM SOLID TUMOR: A MULTICENTER, PHASE I/II, OPEN-LABEL STUDY (PMLM, NCT 05289908)
Authors: Zhenyu Pan, Guozi Yang, Zhuo Wang, Longhai Shen, Tingting Yuan, Xiaochuan Pang, Sijia Li, Lihua Dong
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVES This phase I/II study was to evaluate maximum tolerated dose (MTD) of intrathecal pemetrexed (IP) with vitamin supplementation and antitumor activity for leptomeningeal metastases (LM) from solid tumors. METHODS Phase I study followed the classic 3 + 3 design, with dose escalated from 15 mg. Phase II followed Simon 2-stage design with recommended dose determined in phase I. IP was administered twice per week for 2 weeks (induction therapy), followed by once per week for 4 weeks (consolidation therapy). Vitamin B12 (1000 μg) and folic acid (400 μg, q.d.) were given at the beginning of treatment. Primary end points were MTD in phase I and clinical response rate (CRR) in phase I/II. RESULTS Between Feb 2022 and Jan 2023, 34 patients were enrolled, including non-small cell lung cancer (20), small-cell lung cancer (3), breast cancer (8), others (3). Ten patients were enrolled in phase I. Three of 4 patients receiving IP at 15 mg completed induction and consolidation treatment without dose limiting toxicity (DLT). Two DLT (1 grade 4 hematologic toxicity and 1 grade 5 arachnoiditis) occurred in 6 patients at 20 mg. MTD was determined to be 15 mg. Then 24 patients were enrolled in phase II and given 15 mg of IP. 82.4% (28/34) and 58.8% (20/34) patients completed induction and consolidation therapy, respectively. Adverse events (AEs) rate was 73.5% (25/34). 50% (17/34) patients showed grade ≥ 3 AEs. Overall CRR was 41.2% (14/34), including 10 (29.4%) with improved neurological dysfunction, 11 (32.4%) with CSF cytological response and 4 (11.8%) with neuroimaging improvement. Median survival was 7.6 (range 0.3–13.7) months in phase I, while has not yet been achieved in phase II. CONCLUSION MTD of IP was 15 mg with folic acid and vitamin B12 supplementation. IP is an optimal therapeutic option for LM from solid tumors.
CTIM-11. MRNA AGGREGATES ELICIT RAPID IMMUNOLOGIC RESPONSE AND PSEUDOPROGRESSION IN GLIOBLASTOMA PATIENTS
Authors: Ashley Ghiaseddin, Hector Mendez-Gomez, Maryam Rahman, Anna DeVries, Dingpeng Zhang, Chong Zhao, Marcia Hodik, Jesse Kresak, Tara Massini, Sebastian Gatica, John Ligon, Paul Castillo, Jianping Huang, Natalie Silver, Eugene Hwang, Cassie Kline, Sabine Mueller, Michael Prados, Duane Mitchell, Elias Sayour
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma immunotherapy trials remain limited by heterogeneity and the immunosuppressive tumor microenvironment (TME). To overcome these challenges, we developed a novel cancer immunotherapy that leverages use of mRNA lamellar aggregates (RNA-LPA) encoding for personalized glioblastoma antigens to simultaneously reprogram the GBM TME while inducing tumor specific immunity in the periphery. METHODS In a Phase I trial (PNOC020) with an embedded acceleration titration design (ATD) for patients with newly-diagnosed MGMT unmethylated glioblastoma, we sought to assess whether intravenous administration of RNA-LPAs encoding for pp65 mRNA (tumor associated antigen) mixed with personalized tumor mRNA (extracted and amplified from patient specific biopsies) could activate peripheral immunity while simultaneously reprogramming the GBM TME. All patients received surgical resection with adjuvant chemoradiation followed by escalating doses of RNA-LPA (0.625-1.5 µg/kg). RESULTS We have treated 3 patients on the ATD and one patient on the expanded Phase I trial. In all patients treated to date, RNA-LPAs elicited a rapid response (within hours) characterized by release of cytokines (IL-12, TNF-α, IFN-α), chemokines (CCL2, CCL4, CXCL9-10), increase in plasmacytoid dendritic cells and recruitment of peripheral blood mononuclear cells. Over time there was expansion of antigen specific T cells; T cell receptor (TCR) sequencing pre- and post-infusion demonstrated changes to the most prevalent clonotypes by ~10-20%. In the first subject treated on the expanded phase I trial, we observed significant immunologic response after the fourth vaccine, including 20-fold increase in IFN-γ inducible protein-10. One month after vaccine administration, there was marked increase in the enhancing areas on MRI, which on biopsy demonstrated no viable tumor cells and only reactive gliosis, necrosis, and lymphocytic infiltrates. CONCLUSION RNA-LPAs elicit rapid immune activation in the periphery and reprogram the GBM TME into a proinflammatory milieu as evidenced by tissue confirmed pseudoprogression.